Medical electrical lead having biological surface and methods of making and using same

ABSTRACT

An implantable electrical lead suitable for left sided cardiac placement, the implantable medical electrical lead having an external blood contacting surface having an external coating including a monolayer of at least one biological agent that promotes endothelialization covalently attached to a polymeric lead surface.

RELATED APPLICATIONS

This application is a continuation application of U.S. application Ser.No. 12/977,655, filed Dec. 23, 2010, now allowed, incorporated byreference herein.

BACKGROUND

Medical electrodes have wide clinical application in conjunction with avariety of electronic implantable medical devices such as pacemakers,cardioverter defibrillators, neurostimulators, and ECG monitors. Medicalleads may carry one or more electrodes used for sensing electricalsignals in the body, such as intracardiac electrogram (EGM) signals,electrocardiogram (ECG) signals, and electromyogram (EGM) signals.Electrodes are also used for delivering therapeutic electricalstimulation pulses or for delivering electrical pulses used inelectrophysiological mapping or for other diagnostic purposes.

The typical materials used in the manufacture of medical leads, such as,for example, metals such as platinum, titanium, tantalum, stainlesssteel, iridium, and alloys thereof, are not inherently biocompatible.The response of the body to such a foreign material can be aggressive,resulting in surface-induced thrombus formation. Thrombus formation onthe lead can occur within days. Such thrombi can threaten patienthealth, particularly when they dislodge and travel via the circulatorysystem.

The left side of the heart pumps blood rich in oxygen to supply allparts of the body, while the right side of the heart pumps blood back tothe lungs to pick up more oxygen. Clot formation on a lead placed in thesystemic circulation of the left side of the heart can be clinicallycatastrophic, serving as a source of stroke in patients. While there areclinical applications in which lead placement in the systemiccirculation would be advantageous, such left side placement is currentlyavoided, because of the substantial and potentially devastating riskpresented by surface-induced thrombus formation. Thus, there is aclinical need for improved medical leads that are not prone tosurface-induced thrombus formation and are suitable for left sideplacement.

SUMMARY OF THE INVENTION

The present invention includes an implantable electrical lead having anexternal blood contacting surface having an external coating having amonolayer of at least one biological agent that promotesendothelialization covalently attached to a polymeric lead surface.

The present invention includes an implantable medical electrode havingan external blood contacting surface having an external coating having amonolayer of at least one biological agent that promotesendothelialization covalently attached to a polymeric lead surface.

The present invention includes a medical electrical lead having anexternal blood contacting surface having an external coating having amonolayer of at least one biological agent that promotesendothelialization covalently attached to a polymeric lead surface.

The present invention includes a left side pacing lead having anexternal blood contacting surface having an external coating having amonolayer of at least one biological agent that promotesendothelialization covalently attached to a polymeric lead surface.

The present invention includes a left side sensing lead having anexternal blood contacting surface having an external coating having amonolayer of at least one biological agent that promotesendothelialization covalently attached to a polymeric lead surface.

The present invention includes a medical electrical lead suitable forleft ventricular placement having an external coating having a monolayerof at least one biological agent that promotes endothelializationcovalently attached to a polymeric lead surface.

The present invention includes an endocardial left ventricle lead havingan external coating having a monolayer of at least one biological agentthat promotes endothelialization covalently attached to a polymeric leadsurface.

The present invention also includes implantable medical devicesincluding at least one implantable electrical lead having an externalcoating having a monolayer of at least one biological agent thatpromotes endothelialization covalently attached to a polymeric leadsurface. The present invention includes a system suitable for leftventricular placement, the system including at least one implantableelectrical lead having an external coating having a monolayer of atleast one biological agent that promotes endothelialization covalentlyattached to a polymeric lead surface.

The present invention includes a method for manufacturing a medicalelectrical lead suitable for placement in the left ventricle of theheart, the method including covalently attaching a monolayer coatinghaving at least one biological agent that promotes endothelialization toan external blood contacting polymeric surface of the lead.

The present invention includes a method for implanting leads in a leftchamber of the heart, the implantable electrical lead having an externalblood contacting surface having an external coating having a monolayerof at least one biological agent that promotes endothelializationcovalently attached to a polymeric lead surface. In some aspects, themethod further includes delivering an electrical stimulus to the heartthrough the lead. In some aspects, the method further includes sensingan electrical signal through the lead.

The present invention includes a method for left lead placement, themethod including placing a lead having an external blood contactingsurface having an external coating having a monolayer of at least onebiological agent that promotes endothelialization covalently attached toa polymeric lead surface in the left ventricle of the heart. In someaspects, the method further includes delivering an electrical stimulusto the heart through the lead. In some aspects, the method furtherincludes sensing an electrical signal through the lead.

The present invention includes a method for endothelializing anelectrical lead placed in the left ventricle of the heart, the methodincluding placing a lead having an external blood contacting surfacehaving an external coating having a monolayer of at least one biologicalagent that promotes endothelialization covalently attached to apolymeric lead surface in the left ventricle of the heart. In someaspects, the method further includes delivering an electrical stimulusto the heart through the lead. In some aspects, the method furtherincludes sensing an electrical signal through the lead.

The present invention includes a method for promoting theendothelialization of an electrical lead placed in the left ventricle ofthe heart, the method including placing a lead having an external bloodcontacting surface having an external coating having a monolayer of atleast one biological agent that promotes endothelialization covalentlyattached to a polymeric lead surface in the left ventricle of the heart.In some aspects, the method further includes delivering an electricalstimulus to the heart through the lead. In some aspects, the methodfurther includes sensing an electrical signal through the lead.

In some aspects of the leads, devices, systems, and methods of thepresent invention, an implantable electrical lead includes a stimulationlead. In some aspects, an implantable electrical lead includes a sensinglead. In some aspects, an implantable electrical lead is suitable forplacement in the left ventricle of the heart.

In some aspects of the leads, devices, systems, and methods of thepresent invention, the biological agent includes a growth factor. Insome aspects, the biological agent includes a polypeptide. In someaspects, the polypeptide includes collagen.

In some aspects of the leads, devices, systems, and methods of thepresent invention, the biological agent includes a peptide. In someaspects, the biological agent includes a polysaccharide.

In some aspects of the leads, devices, systems, and methods of thepresent invention, the biological agent includes an antibody. In someaspects, the antibody includes an antibody to an endothelial cellsurface marker. In some aspects, the antibody includes an anti-CD34antibody. In some aspects, the antibody includes an anti-human CD34antibody.

In some aspects of the leads, devices, systems, and methods of thepresent invention, a biological agent covalently is attached to thepolymeric lead surface by activation by N-hydroxysuccinimide (NHS) andN-ethyl-N′-dimethyl-aminopropyl-carbodiimide hydrochloride (EDC).

In some aspects of the leads, devices, systems, and methods of thepresent invention, a biological agent is covalently attached to thepolymeric lead surface by a dextran linker.

In some aspects of the leads, devices, systems, and methods of thepresent invention, a biological agent is covalently attached to thepolymeric lead surface by sodium periodate chemistry.

In some aspects of the leads, devices, systems, and methods of thepresent invention, a biological agent is covalently attached to thepolymeric lead surface by a UV photo linker. The above summary of thepresent invention is not intended to describe each disclosed embodimentor every implementation of the present invention. The description thatfollows more particularly exemplifies illustrative embodiments. Inseveral places throughout the application, guidance is provided throughlists of examples, which examples can be used in various combinations.In each instance, the recited list serves only as a representative groupand should not be interpreted as an exclusive list. For any methoddisclosed herein that includes discrete steps, the steps may beconducted in any feasible order. And, as appropriate, any combination oftwo or more steps may be conducted simultaneously.

Unless otherwise indicated, all numbers expressing quantities ofcomponents, molecular weights, and so forth used in the specificationand claims are to be understood as being modified in all instances bythe term “about.” Accordingly, unless otherwise indicated to thecontrary, the numerical parameters set forth in the specification andclaims are approximations that may vary depending upon the desiredproperties sought to be obtained by the present invention. At the veryleast, and not as an attempt to limit the doctrine of equivalents to thescope of the claims, each numerical parameter should at least beconstrued in light of the number of reported significant digits and byapplying ordinary rounding techniques.

The term “and/or” means one or all of the listed elements or acombination of any two or more of the listed elements.

The words “preferred” and “preferably” refer to embodiments of theinvention that may afford certain benefits, under certain circumstances.However, other embodiments may also be preferred, under the same orother circumstances. Furthermore, the recitation of one or morepreferred embodiments does not imply that other embodiments are notuseful, and is not intended to exclude other embodiments from the scopeof the invention.

The terms “comprises” and variations thereof do not have a limitingmeaning where these terms appear in the description and claims.

Unless otherwise specified, “a,” “an,” “the,” and “at least one” areused interchangeably and mean one or more than one.

Also, herein, the recitations of numerical ranges by endpoints includeall numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2,2.75, 3, 3.80, 4, 5, etc.).

Notwithstanding that the numerical ranges and parameters setting forththe broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. All numerical values, however, inherently contain a rangenecessarily resulting from the standard deviation found in theirrespective testing measurements.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a schematic diagram of endocardial left ventricular leadplacement in relation to a patient's heart.

FIG. 2A is a plan view of one embodiment of a medical electrical lead.

FIG. 2B is a sectional view of an electrical lead provided with acovalently bonded biological lead outer insulation surface.

FIG. 3 presents an overview covalent attachment to lead outer surface byactivation of reactive compounds N-hydroxysuccinimide (NHS) andN-ethyl-N′-dimethyl-aminopropyl-carbodiimide hydrochloride (EDC).

FIG. 4 presents an overview covalent attachment to lead outer surfacewith use of a dextran linker and sodium periodate chemistry.

FIG. 5 presents an overview covalent attachment to lead outer surfacewith UV photo-linker technology.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS OF THE PRESENTINVENTION

The present invention provides implantable medical electrical leads thatare suitable for left sided cardiac placement in oxygenated, arterialblood. The medical electrical leads described herein have an externalblood contacting surface that includes an external monolayer coating ofat least one biological agent that promotes endothelializationcovalently attached to a polymeric lead surface. This external bloodcontacting surface promotes the endothelialization of the lead. That is,such leads, when placed in contact with the circulatory system, bind,recruit and/or retain circulating endothelial cells (ECs) and/orendothelial progenitors cells (EPCs). Vascular endothelial cells arethin, flattened epithelial cells that form a thin layer on the interiorsurfaces of all blood vessels and lymphatics (lymph vessels) throughoutthe entire circulatory system. The thin cell layer formed by endothelialcells is called the endothelium. Both blood and lymphatic capillarieshave of a single layer of endothelial cells on the vessel walls that arein contact with circulating blood or lymph. Endothelial cells possessintrinsic characteristics that prevent the formation of blood clots onendothelial surfaces. Thus, the endothelium provides an anticoagulantbarrier between the vessel wall and blood and plays a major role ininhibiting thrombosis.

The coated medical electrical leads described herein, when placed incontact with the circulatory system, become endothelialized, that is,become covered, in whole or in part, with a layer of viable endothelialcells endothelial cells. This endothelial cell layer serves as ananti-thrombogenic barrier on the surface of the medical electrical lead.The overgrowth and coverage of the lead surface with endothelial cellssignificantly reduces the thrombogenic potential of the leads. Suchendothelialization of the leads results in the reduced adherance ofblood components to the lead surface, inhibiting of the formation ofblot clots on the lead surface and making such medical electrical leadssuitable for left sided cardiac placement in oxygenated, arterial blood.As used herein, the term “endothelial cells” includes endothelial cellsat any developmental stage, from endothelial cell progenitors to fullydifferentiated, mature endothelial cells.

There is currently great concern and clinical avoidance of placingmedical electrical leads in the left atrium or left ventricle of theheart. The concern with such left sided placement of a lead is thepotential for formation of thromboemboli. Since the left side of theheart pumps the oxygenated blood to all parts of the body, even a smallthromboembolus in the systemic circulation can be clinicallycatastrophic. Possible thromboembolic complications include boththromboembolic cerebral vascular accident (CVA; also referred to as a“stroke”) and non-cerebral thromboembolic complications, such as,ischemic lung, splenic infarct, renal infact, and ischemic bowel. Themedical electrical leads described herein present a reduced risk of suchthromboembolic complications.

The heart is a muscle and functions primarily as a double-sided pump.The left side of the heart pumps blood rich in oxygen to supply allparts of the body, while the right side of the heart pumps blood back tothe lungs to pick up more oxygen. There are four chambers, two upperchambers called the left and the right atria and two lower chambersknown as the right and left ventricles. Separating these upper and lowerchambers there are valves that passively open and close to direct theflow of blood. The left atrium is the left upper chamber of the heartthat receives oxygenated blood from the lungs via the pulmonary veins.The left ventricle is the left lower chamber of the heart, whichreceives oxygenated blood from the left atrium and pumps it through theaorta to the body. The right atrium is the right upper chamber of theheart, which receives deoxygenated blood from the systemic venoussystem. The right ventricle is the right lower chamber of the heart,which receives deoxygenated blood from the right atrium and pumps it tothe lungs via the pulmonary artery. The left ventricle performs the mostwork and is the strongest of the chambers because it ejects blood intothe aorta, the main pipeline that supplies oxygenated blood to theentire body. Coated medical electrical leads as described herein, aresuitable for placement in the left ventricle and/or the left atrium (seeFIG. 1), also referred to herein as the “left side.” Coated medicalelectrical leads as described herein are also suitable for placement inother locations circulating oxygenated arterial blood, such as forexample, coronary arteries, aortic arch vasculature, or peripheralarteries. Coated medical electrical leads as described herein are alsosuitable for placement in other locations, such as for example, rightatrium, coronary sinus, or epidural space of the spinal cord.

As used herein, a thrombus (also referred to herein as “thrombi” or“blood clot”) is an aggregate of a network of fibrin, platelets, andother blood components. “Thrombosis” is the formation of such a bloodclot. When a thrombus becomes dislodged from the surface on which itformed and circulates in the bloodstream it is called a thromboemboli.As used herein, a thromboembolism is a blood clot which circulates inthe bloodstream and blocks a vessel. As used herein, “thrombogenic” iscausing, or having the potential to cause, the formation of a thrombus.The endothelialized blood contacting surface of the medical electricalleads described herein prevent the formation of blood clots on leadsurfaces and the leads demonstrate a decreased potential for theformation of harmful blood clots.

An implantable medical electrical lead generally includes an elongated,flexible insulating lead body extending from a proximal end to a distalend, with one or more inner conductors extending through lumens formedin the body and one or more exposed electrodes connected to the distalends of the conductors. The proximal end is configured to be operativelyconnected to a pulse generator via a connector. While the electrodes canhave any electrode configuration as is known in the art, FIG. 2A is aplan view of one embodiment of a medical electrical lead. Lead 4includes an elongated lead body 110 extending between a distal end 115and a proximal end 116. A tip electrode 112 is provided at distal leadend. A ring electrode 114 is spaced proximally from tip electrode 112.Each electrode 112 and 114 is individually coupled to an insulatedconductor extending through lead body 115 to a connector 118, 122 or 124included in proximal connector assembly 120. Proximal connector assembly120 is adapted to be inserted in a connector bore provided in animplantable medical device for electrically connecting electrodes 112and 114 to electronics included in, for example, and IMD.

Implantable medical leads have many uses. For example, an implantableelectrical medical leads as disclosed herein may be a sensing lead or astimulation lead. As used herein, a sensing lead carries one or moreelectrodes used for sensing physiological signals in the body. As usedherein, a stimulation lead delivers a therapeutic electrical stimulationpulse, for example, in pacing therapy to the heart, and/or deliverselectrical pulses used in electrophysiological mapping or for otherdiagnostic purposes. A medical electrical lead may be unipolar, bipolar,or multi-polar depending upon the type of therapy to be delivered.

A medical electrical lead as disclosed herein may have an insulativeouter sheath (also referred to herein as an outer insulation). Such anouter sheath may be a polymeric material such as silicone, polyurethane(including, but not limited to the polyether urethanes Pellethane 80Aand Pellethane 55D, manufactured by Dow Chemical Company),polytetrafluoroethylene (PTFE), expanded polytetrafluoroethylene(ePTFE), ETFE, polyethylene, polypropylene and other polymer coatings.Such polymeric insulative outer sheaths may be applied by conventionalmeans. With the present invention, the outer insulative sheath of amedical electrical lead is coated with at least one biological agentthat promotes endothelialization of the surface of the medicalelectrical lead. FIG. 2B is a partial cross-sectional view of a coatedmedical electrical lead, according to an embodiment of the presentinvention. The one or more biological agents that promoteendothelialization may be covalently attached to the insulative outersheath of the lead body as a monolayer.

In preferred embodiments, the one or more biological agent that promotesendothelialization may be covalently coupled to the polymeric materialof the insulative outer sheath of the lead body. Any suitable processmay be employed to covalently bond a biological agent to the insulativeouter sheath of a lead body. See, for example, U.S. Pat. Nos. 4,521,564,5,308,641, 5,811,151, 5,866,113, 5,925,552, 6,033,719, 6,096,070,6,159,531, 6,961,610, 7,632,234, and U.S. Patent Applications2003/0059537, 2006/0240072, and 2008/0063627. Also included are methodsof modifying the outer surface of an implantable medical electrical leadby covalently attaching one or more biological agents that promoteendothelialization to the polymeric material of the outer insulativesheath of the lead body.

In other embodiments, the one or more biological agents that promoteendothelialization may be applied to the insulative outer sheath of thelead body in a manner other than covalent attachment. For example, oneor more biological agents that promote endothelialization may be appliedto the insulative outer sheath of the lead body by coating, immersion,dipping, spraying, vapor deposition, plasma deposition, and the like.

The method of covalently attaching a biological agent that promotesendothelialization will differ depending on the nature of the biologicalagent and/or the material of polymeric coating of the outer sheath ofthe lead. When the agent is an antibody or protein, covalently bondingthe protein to the surface with outer sheath with bi-functionalmolecules such as glutaraldehyde, carbodiimides, biotin-avidin, andother molecules with one or more functional groups on each of at leasttwo ends as are well known to those skilled in the art. Additionally,bi-functional spacer molecules such as N-hydroxysuccinimide derivatizedpolyethylene glycols may be used to bind the protein.

Covalent attachment may be accomplished by one or more reactivecompounds, such as, for example, activation by N-hydroxysuccinimide(NHS) and N-ethyl-N′-dimethyl-aminopropyl-carbodiimide hydrochloride(EDC), as described in FIG. 3. Additional reactive groups may include(3-aminopropyl)trimethoxysilane (APTS), epichlorohydrin (EPC), starPEG-succinimidyl succinate, dextran (DEX), and/or polyacrylic acid (see,for example, U.S. Published Patent Application Serial No. 2009/0270962).The outer sheath of the lead may be, for example, a polymeric materialhaving surface modifying end groups that facilitate the attachment of abiological agent. For example, a branched polyethylene oxide (PEO) orstar PEO, as described, for example, in U.S. Pat. No. 6,961,610, mayserve as the polymer outer sheath of a lead. These compounds arecommercially available, for example, from Sigma-Aldrich located in St.Louis, Mo. Covalent attachment may also be accomplished by the use of adextran linker and sodium periodate chemistry, as described in FIG. 4.

Covalent attachment may be accomplished by photo-coupling techniques,via one or more activated photoreactive groups that are activated andreacted to bond one or more biological agents to the outer sheath of thelead. “Activated” means that the photoreactive groups have been treatedwith an activating source of radiation, thereby having excited thegroups to an active state that resulted in bonding the groups to thetissue graft material. Photoreactive groups, broadly defined, are groupsthat respond to specific applied external light energy to undergo activespecie generation with resultant covalent bonding to a target.Photoreactive groups are those groups of atoms in a molecule that retaintheir covalent bonds unchanged under conditions of storage but which,upon activation, form covalent bonds with other molecules. Thephotoreactive groups generate active species such as free radicals,nitrenes, carbenes, and excited states of ketones upon absorption ofexternal electromagnetic or kinetic (thermal) energy. Photoreactivegroups may be chosen to be responsive to various portions of theelectromagnetic spectrum. For example, those that are responsive to theultraviolet and visible portions of the spectrum may be used. Suchphotoreactive groups are well known in the art (see, for example, U.S.Patent Application Serial No. 2008/0063627). Photoreactive groups,including, but not limited to the UV photo-linker technology describedin FIG. 5.

As used herein, a biological agent is a biomolecule that engages in abiological activity. A biological agent that promotes endothelializationmay be, for example, a polypeptide, a peptide, a polysaccharide, anantibody, or an aptamer. As used herein, a polypeptide (also referred toherein as a “protein”) is a chain of fifty or more amino acids. As usedherein, a peptide is a chain of at least two, but fewer than fifty aminoacids.

A biological agent that promotes endothelialization may be, for example,a peptide. Such peptides include, but are not limited to, peptidescontaining the Arg-Gly-Asp (RGD) fibronectin-derived attachment peptideand peptides containing the laminin-derived adhesive peptidesCys-Asp-Pro-Gly-Tyr-Ile-Gly-Ser-Arg ((CDPGYIGSR); (SEQ ID NO:1)),Tyr-Ile-Gly-Ser-Arg ((YIGSR); (SEQ ID NO:2)), or Tyr-Ile-Gly-Ser-Arg-Gly((YIGSRG); (SEQ ID NO:3)).

A biological agent that promotes endothelialization may be, for example,a polypeptide. Such polypeptides include, but are not limited to,extracellular matrix (ECM) proteins, such as, for example, collagen,laminin, fibronectin, vitronectin, or matrigel; growth factors, such asfor example, basic fibroblast growth factor (bFGF), transforming growthfactor-ß (TGF-β), vascular endothelial growth factor (VEGF), orgranulocyte colony stimulating factor (G-CSF); cytokines; or hormones.In some preferred embodiments, the polypeptide is collagen, including,but not limited to, collagen I and/or collagen IV. Also included arepolypeptides containing the RGD, CDPGYIGSR (SEQ ID NO:1), YIGSR (SEQ IDNO:2), or YIGSRG (SEQ ID NO:3) attachment recognition sequences.

A biological agent that promotes endothelialization may be, for example,a polysaccharide, such as for example, amylose, maltodextrin,amylopectin, starch, dextran, hyaluronic acid, heparin, chondroitinsulfate, dermatan sulfate, heparan sulfate, keratan sulfate, dextransulfate, pentosan polysulfate, or chitosan. In some preferredembodiments, the polysaccharide is hyaluronic acid (HA; also known ashyalurnan or hyaluronate), including, for example, a mixture of large HAfragments (with a molecular weight of greater than about 10 kiloDalton(kDa) and less than about 1 megadalton (Mda)), high molecular weight(HMW) HA (with a molecular weight of greater than about 1000 kDa), anoligomeric HA mixture (HA-o) (with, for example, a molecular weight ofabout 0.75 to about 10 kDa), HA-1500 (with a molecular weight of about1500 kDa), HA 1500-3000 (with a molecular weight range of about 1500daltons to about 3000 daltons), HA-1500 (with a molecular weight ofabout 1500 Da), and purified oligomers of HA, such as HA-6-mer or HA12-mer.

A biological agent that promotes endothelialization may be, for example,an apatamer. Aptamers are single stranded DNA or RNA polynucleotides(ssDNA or ssRNA), generally about 70 to 80 nucleotides in length, thatcan bind with a high affinity and specificity to a target molecule, suchas for example, a target molecule on the surface of an endothelial cellor an endothelial progenitor cell, including, but not limited to,VE-cadherin; CD146 (also known as MCAM or MUC18); CD31 (also known asPECAM-1); CD117 (also known as stem cell receptor factor (SCF R)); CD34(also known as hemopoietic progenitor cell antigen 1 (HPCA1) andgp105-120); Tie-2; CD45; vascular endothelial growth factor receptor 1(VEGF R1); vascular endothelial growth factor receptor 2 (VEGF R2; alsoknown as KDR and Flk-1); CXCR4; VEGF R3 (also known as Flt-4); CD133;and E-selectin. Aptamers are generated through an iterative in vitroselection and amplification process called SELEX (systematic evolutionof ligands by exponential enrichment).

A biological agent that promotes endothelialization may be, for example,an antibody. Such an antibody may be, for example, an antibody thatbinds to a surface molecule on circulating endothelial progenitor cells.Endothelial progenitor cells (EPCs) are a type of predifferentiatedadult stem cell with the potential to proliferate and differentiate intomature endothelial cells. EPCs are mainly located in the bone marrow,but circulate at low concentrations in the peripheral blood of healthyadults. The concentration of EPCs in peripheral blood can be increasedby mobilization with growth factors such as, for example, granulocytestimulating factor (G-CSF) or VEGF. EPCs have the potential toproliferate and differentiate mature endothelial cells, prompting theprocess of endothelialization, with the capacity to repair or form newendothelium. See, for example, Avci-Adali et al., 2008, Biomaterials;29:3936-3945; Chong et al., 2010, Tissue Eng Part A; 16(8):2485-2495; Liet al., 2010, J Biomed Mater Res A; 94(4):1283-93; Lin et al., 2010,Biomaterials; 31: 4017-4025; and Wendel et al., 2010, Int J Cardiol;145(1):115-7.

Markers for endothelial progenitor cells include, but are not limitedto, VE-cadherin; CD146 (also known as MCAM or MUC18); CD31 (also knownas PECAM-1); CD117 (also know as stem cell receptor factor (SCF R));CD34 (also known as hemopoietic progenitor cell antigen 1 (HPCA1) andgp105-120); Tie-2; CD45; VEGF R2 (also know as KDR and Flk-1); CXCR4;and VEGF R3 (also known as Flt-4). In some embodiments, the antibody maybe a human antibody or a humanized antibody.

In some preferred embodiments, the antibody is an antibody to CD34,including, but not limited to, an antibody to human CD34. CD34 is amonomeric cell surface antigen with a molecular mass of approximately110 kD that is selectively expressed on human hematopoietic progenitorcells. Although its precise biological function remains unknown, thepattern of expression of CD34 suggest that it plays a significant rolein early hematopoieses and it is used a surface marker for very earlyhematopoietic stem cells. Cells expressing CD34 (CD34+ cell) arenormally found in the umbilical cord and bone marrow as hematopoieticcells, a subset of mesenchymal stem cells, endothelial progenitor cells,and endothelial cells of blood vessels. Antibodies to CD34 includemonoclonal antibodies 4C8, BI-3C5 (Santa Cruz Biotechnology, Inc.);IC-H3; MY10; 188.27; Clone 4H11 (BioLegend, San Diego, Calif.); Clone561 (BioLegend, San Diego, Calif.); Clone 581 (BioLegend, San Diego,Calif.); and rabbit monoclonal CD34 antibodies clone ID EP373Y(Epitomics, Inc., Burlingame, Calif.) and Clone ID EPR2999 (Epitomics,Inc., Burlingame, Calif.).

A biological agent that promotes endothelialization may be, for example,a ligand to a receptor or other surface protein on the surface ofcirculating endothelial progenitor cells, such as, for example, a ligandto VE-cadherin; CD146 (also known as MCAM or MUC18); CD31 (also known asPECAM-1); CD117 (also known as stem cell receptor factor (SCF R)); CD34(also known as hemopoietic progenitor cell antigen 1 (HPCA1) andgp105-120); Tie-2; CD45; VEGF R2 (also known as KDR and Flk-1); CXCR4;and VEGF R3 (also known as Flt-4). In some preferred embodiments, thebiological agent that promotes endothelialization is a ligand to CD34.

In some embodiments, a medical electrical lead is coated with onebiological agent that promotes endothelialization. In some embodiments,a medical electrical lead is coated with two or more biological agentsthat promote endothelialization, including, but not limited to any two,three, four, five, or more of the biological agent that promoteendothelialization described herein. A medical electrical lead may befurther coated with additional compounds.

It is understood that the present invention is not limited for use incardiac leads. Other uses of the coated leads described herein includeuse in other locations where thrombus formation is problematic and/orwhere the endothelialization of the leads would be clinicallyadvantageous. Medical electrical leads, as described herein, may forexample, be used for neurostimulation. In some embodiments, medicalelectrical leads may be chronically implanted in a subject.

Medical electrical leads, as described herein, may be used anyappropriate diagnostic or therapeutic procedure, including, but notlimited to, use in conjunction with systems, devices, methods, andapparatus in which the transmission and/or reception of one or moreelectrical impulses in a subject is desired. For example, medicalelectrical leads, as described herein, may be used in any of a varietyof therapeutic methods. Medical electrical leads as described herein maybe used along with a device that is implantable (in whole or in part),also referred to as an implantable medical device (IMD). An IMD may be,for example, an implantable pulse generator (IPG) that deliverselectronic pacing therapy. Any of a wide variety of implantableelectronic pulse generators may be used, including, but not limited to,pacemaker, implantable cardioverter defibrillator (ICD), cardiacresynchronization therapy (CRT), cardiac resynchronization therapydefibrillation device (CRT-D), subcutaneous ICD (SubQ ICD),intravascular pacemaker/ICD, and/or miniaturized leadless pacemaker. Apacemaker may include, but is not limited to, EnRhythm® pacemaker,Adapta® pacemaker, Versa™ pacemaker, Sensia™ pacemaker, Thera®pacemaker, Prodigy® pacemaker, Priva® pacemaker, and Minuet® pacemaker,all available from Medtronic Inc., Minneapolis, Minn. An IMD may, forexample, provide cardiac monitoring capabilities, alternate cardiactherapies, non-cardiac monitoring and/or non-cardiac therapies.

As used herein, the term “subject” includes, but is not limited to,humans and non-human vertebrates. In preferred embodiments, a subject isa mammal, particularly a human. A subject may be an individual. Asubject may be a patient. Non-human vertebrates include livestockanimals, companion animals, and laboratory animals. Non-human subjectsalso include non-human primates as well as rodents, such as, but notlimited to, a rat or a mouse. Non-human subjects also include, withoutlimitation, chickens, horses, cows, pigs, goats, dogs, cats, guineapigs, hamsters, mink, and rabbits.

The methods of the present invention include in vitro, ex vivo, and invivo methods. As used herein “in vitro” is in cell culture and “in vivo”is within the body of a subject.

A coated medical electrical lead as described herein may be placedwithin the heart of a subject. That is, a heart having an epicardialsurface and disposed within a torso.

The endothelialization of a coated medical electrical lead may bemonitored in vivo, for example, as described in the examples includedherewith, or in vitro, for example, by testing for the adhesion ofisolated human endothelial cells, or progenitors thereof, to a lead.

As used herein, “isolated” refers to material that has been eitherremoved from its natural environment (e.g., the natural environment ifit is naturally occurring), produced using recombinant techniques, orchemically or enzymatically synthesized, and thus is altered “by thehand of man” from its natural state.

The present invention is illustrated by the following examples. It is tobe understood that the particular examples, materials, amounts, andprocedures are to be interpreted broadly in accordance with the scopeand spirit of the invention as set forth herein.

EXAMPLES Example 1 Endothelialization of Collagen Coated Leads Materialand Methods

Test Animals. Six adult purpose-bred rabbits of either sex,weighing >3.0 kg at the time of surgery, were used in this study.

Study Design. The study consisted of two groups of three rabbits each.One group of three rabbits received a single uncoated aorta tubing(control group), while a second group of three rabbits received a coatedaortic tubing with a photografted collagen monolayer. The aortic tubingswere implanted via a left carotid artery stick. All rabbits wereeuthanized on postoperative day 28. At the time of necropsy and tissueanalysis, the pathology was blinded towards the groupings.

Implant Materials. The aortic tubings were 4 French, 6 inch longpolyurethane Elasthane 55D tubings (without wax), with an MP35N innercoil, and sealed at both ends with silicone medical adhesive. Coatedaortic tubings received a photografted Collagen I monolayer coating.Control aortic tubings were uncoated. Aortic tubings were notelectrically active.

Necropsy Methods and Tissue Trimming. The skin over the thorax and theneck was removed, the leads along the neck were located, and the rightside of the rib cage was opened. After reflection of the lungs, thepericardium was incised and the epicardial surface of the heartinspected. The aorta was also visualized. The left side of the heart wasalso opened and examined. After the aorta was opened longitudinally, thetubing was located, and imaged in situ. Heart, aorta, and aortic tubingwere immersed in 10% neutral-buffered formalin. The major organs withoutthe brain were examined.

Histological review of tubing was performed. First, the metal coil wasextracted. Then the distal tips were cut off and were transferred intoKarnovsky solution for post fixation. These tips were forwarded forconfocal microscopy and scanning electron microscopy (SEM). Ahistological review was also performed on the adjacent portion of theaortic tubing that was free floating in the LV or aorta (and notsurrounded by carotid artery); it was cut longitudinally in two halvesand forwarded for histology. Remainder of fixed tissue samples werereturned to formalin for continued preservation.

Slide Preparation/Histology Methods. Specimens within labeled histologycassettes were dehydrated through a graded series of alcohol andembedded in paraffin. Three to 5 μm thick paraffin sections were cutwith a microtome, mounted on glass slides, deparaffinized, and stainedwith hematoxylin and eosin (HE) to evaluate morphology. A serial sectionof the tissue sections was stained with Trichrome Masson to evaluateconnective tissue. Microscopic measurements were performed by using theNikon Digital Sight Camera (Model DS-5M). Brightfield histology imageswere captured with a Nikon Digital Sight Camera that was attached to aNikon Ecclipse 801 brightfield microscope.

Results

Gross images and histology images were obtained for the aortic tubingsafter formalin fixation. All the three coated tubings demonstratedendothelial cell overgrowth, while only one of the three uncoatedcontrol tubings demonstrated limited endothelial cell overgrowth. Two ofthe three uncoated tubings showed no endothelial cell overgrowth.Confocal microscopy results and SEM yielded similar results asbrightfield histology. Thus, a photografted collagen monolayer onpolyurethane 55D leads, implanted in aorta in six rabbits fortwenty-eight days, promoted endotheliazation as compared to uncoatedpolyurethane 55D leads.

Following procedures described above, the endothelialization of leadscoated with anti-CD34 antibodies will also be determined.

The complete disclosure of all patents, patent applications, andpublications, and electronically available material (including, forinstance, nucleotide sequence submissions in, e.g., GenBank and RefSeq,and amino acid sequence submissions in, e.g., SwissProt, PIR, PRF, PDB,and translations from annotated coding regions in GenBank and RefSeq)cited herein are incorporated by reference. In the event that anyinconsistency exists between the disclosure of the present applicationand the disclosure(s) of any document incorporated herein by reference,the disclosure of the present application shall govern. The foregoingdetailed description and examples have been given for clarity ofunderstanding only. No unnecessary limitations are to be understoodtherefrom. The invention is not limited to the exact details shown anddescribed, for variations obvious to one skilled in the art will beincluded within the invention defined by the claims. All headings arefor the convenience of the reader and should not be used to limit themeaning of the text that follows the heading, unless so specified.

What is claimed is:
 1. An implantable medical device including at leastone implantable medical electrode suitable for placement in the leftventricle of the heart comprising an external blood contacting surfacecomprising an external coating comprising a monolayer of at least onebiological agent that promotes endothelialization covalently attached toa polymeric surface, the biological agent comprising a polypeptide, thepolypeptide comprising collagen.
 2. The implantable medical device ofclaim 1 wherein the at least one electrode is a stimulation electrode.3. The implantable medical device of claim 1 wherein the at least oneelectrode is a sensing electrode.
 4. An implantable medical deviceincluding at least one implantable medical electrode suitable forplacement in the left ventricle of the heart comprising an externalblood contacting surface comprising an external coating comprising amonolayer of at least one biological agent that promotesendothelialization covalently attached to a polymeric surface, thebiological agent comprising a polysaccharide.
 5. The implantable medicaldevice of claim 4, wherein the at least one electrode is a stimulationelectrode.
 6. The implantable medical device of claim 5, wherein the atleast one electrode is a sensing electrode.
 7. An implantable medicaldevice including at least one implantable medical electrode suitable forplacement in the left ventricle of the heart comprising an externalblood contacting surface comprising an external coating comprising amonolayer of at least one biological agent that promotesendothelialization covalently attached to a polymeric surface, thebiological agent comprising an antibody.
 8. The implantable medicaldevice of claim 7, the antibody comprising an antibody to an endothelialcell surface marker.
 9. The implantable medical device of claim 8, theantibody comprising an anti-CD34 antibody.
 10. The implantable medicaldevice of claim 7, wherein the at least one electrode is a stimulationelectrode.
 11. The implantable medical device of claim 7, wherein the atleast one electrode is a sensing electrode.
 12. The implantable medicaldevice of claim 1 wherein the at least one electrode is a pacingelectrode.
 13. The implantable medical device of claim 4 wherein the atleast one electrode is a pacing electrode.
 14. The implantable medicaldevice of claim 8 wherein the at least one electrode is a pacingelectrode.
 15. The implantable medical device of claim 12 wherein theimplantable medical device is a leadless pacemaker.
 16. The implantablemedical device of claim 13 wherein the implantable medical device is aleadless pacemaker.
 17. The implantable medical device of claim 14wherein the implantable medical device is a leadless pacemaker.